Ontology highlight
ABSTRACT:
PROVIDER: PRJNA988676 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25056200_1.fastq.gz | Fastqsanger.gz | |||
| SRR25056200_2.fastq.gz | Fastqsanger.gz | |||
| SRR25056201_1.fastq.gz | Fastqsanger.gz | |||
| SRR25056201_2.fastq.gz | Fastqsanger.gz | |||
| SRR25056202_1.fastq.gz | Fastqsanger.gz |
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Project description:Proviral location affects cognate peptide-induced virus production and immune recognition of 2 HIV-1-infected T cell clones
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Project description:Clonal expansion of HIV infected CD4+ T cells is a barrier to HIV eradication. We previously described a marked reduction in the frequency of the most clonally expanded infected CD4+ T cells in an individual with elite control (ES24) after initiating chemoradiation for metastatic lung cancer with a regimen that included paclitaxel and carboplatin. We tested the hypothesis that this phenomenon was due to a higher susceptibility to the chemotherapeutic drugs of CD4+ T cell clones that were sustained by active proliferation. We studied a CD4+ T cell clone with replication-competent provirus integrated into the ZNF721/ABCA11P genes, termed ZNF721i. We stimulated the clone with its cognate peptide and then exposed the cells to paclitaxel and/or carboplatin or the antiproliferative drug, mycophenolate mofetil. While treatment of cells with the cognate peptide alone led to a marked expansion of the ZNF721i clone, treatment with the cognate peptide followed by culture with either paclitaxel or mycophenolate mofetil abrogated this process. The drugs did not affect the proliferation of other CD4+ T cell clones that were not specific for the cognate peptide. This strategy of antigen-specific stimulation followed by treatment with an antiproliferative agent may lead to the selective elimination of clonally expanded HIV-infected cells.
2025-08-25 | GSE305896 | GEO
Project description:In this study, we determined the effect of proviral inducibility on CD8+ T cell recognition of HIV-infected clones. We showed that a T cell clone containing a provirus integrated in relatively transcriptionally inactive site was much less recognized by CD8+ T cells than a T cell clone containing a provirus that was integrated into a trancriptionally active site.
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Project description:Despite antiretroviral therapy (ART), HIV-1 persists in latently-infected CD4+ T cells, preventing cure. Antigen (Ag) drives proliferation of infected cells, preventing latent reservoir decay. However, the relationship between antigen recognition and HIV-1 gene expression is poorly understood since most studies of latency reversal use agents that induce non-specific global T cell activation. Here, we isolated rare CD4+ T cells responding to cytomegalovirus (CMV) or HIV-1 Gag antigens from participants on long-term ART and assessed T cell activation and HIV-1 RNA expression upon co-culture with autologous dendritic cells (DCs) presenting cognate antigens. Physiological presentation of cognate antigens induced broad T cell activation (median 42-fold increase in CD154+CD69+ cells) and significantly increased HIV-1 transcription (median 4-fold), mostly through the induction of rare cells with higher viral expression. Thus, despite low proviral inducibility, physiologic antigen recognition can promote HIV-1 expression, potentially contributing to spontaneous reservoir activity on ART and viral rebound upon ART interruption. Additionally, we observed striking differences in the transcriptome profiles of Ag-responding CD4+ T cells after stimulations with Ag or global T cell activators. This analysis revealed quantitative differences between NFAT and NFkB target genes and may guide future approaches to Ag-mediated HIV-1 latency reversal.
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Project description:Selective targeting of HIV infected clones by cognate peptide stimulation and antiproliferative drugs
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Project description:The reservoir of latently HIV-1 infected cells is heterogeneous. To achieve an HIV-1 cure the reservoir of activatable proviruses should be removed, whereas permanently silenced proviruses may be tolerated. We have developed a method to assess the proviral nuclear microenvironment in single cells. Latently HIV-1 infected cells were transduced with a zinc finger protein specifically binding to the HIV-1 promoter, producing a fluorescent signal as the viral transactivator Tat is recruited to the HIV-1 promoter. In these cells we assessed the proviral chromatin composition simultaneously with the proviral activation. By linking the Tat promoter recruitment to viral activation, we dissected the mechanisms of HIV-1 reactivation and the consequences of HIV-1 production. A pulse of promoter-associated Tat was identified that contrasts to the continuous production of viral proteins. As expected, promoter H3K4me3 led to massive expression of the provirus following T cell stimulation. However, the activation induced cell cycle arrest and death resulted in an expanded surviving cell fraction with proviruses encapsulated in repressive chromatin. Further, this model can be used to reveal mechanisms of action of small molecules. In a proof-of-concept study we determine the effect of CBP/P300-inhibitor GNE049. We found that only active enhancers, associated with H3K4me1 and H3K27ac, efficiently recruit Tat, as GNE049 that specifically inhibits enhancer H3K27ac also depletes promoter Tat. Despite the absence of Tat, HIV-1 latency reversal still occurred. Single cell assessment of the chromatin composition of the latent HIV-1 proviruses revealed how T cell stimulation modulates the proviral activity and the subsequent fate of the infected cell.
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Project description:Human immunodeficiency virus (HIV) infection is a chronic condition, where viral DNA integrates into the genome. The fate of the provirus determines the infection course. Latently infected cells form a persistent, heterogeneous reservoir. The reservoir that reinstates an active infection comprises cells with intact provirus that can be reactivated. We confirmed that latent cells from patients exhibited active transcription throughout the provirus. To find transcriptional determinants, we characterized the establishment and maintenance of latency during proviral chromatin maturation in primary CD4+ T-cells for four months after HIV infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible and lost activation potential. In a subset of infected cells, active marks (i.e., H3K27ac) remained detectable, even after prolonged proviral silencing. After T-cell activation, the proviral activation occurred uniquely in cells with H3K27ac-marked proviruses. Our observations suggested that, after transient proviral activation, cells were actively returned to latency.
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